{"entity":{"id":"grade-3-net","kind":"cancer","name":"Grade 3 well-differentiated neuroendocrine tumour","aka":["NET G3","Grade 3 NET","Well-differentiated grade 3 neuroendocrine tumour","High-grade well-differentiated NET"],"tldr":"Grade 3 well-differentiated neuroendocrine tumours divide fast enough to be called grade 3 yet still look and behave like their slower relatives rather than like neuroendocrine carcinoma. Recognised as separate since 2017, they keep the somatostatin receptor, respond less well to platinum chemotherapy, and in the NETTER-2 trial were among the first treated with lutetium-177 dotatate up front.","summary":"Until 2017 every neuroendocrine neoplasm with a Ki-67 above 20 percent was called neuroendocrine carcinoma and treated like small-cell lung cancer. Pathologists noticed that some of these tumours kept the organoid architecture, uniform nuclei and somatostatin receptor expression of well-differentiated tumours, and that their patients lived far longer than those with carcinoma. Multicentre series, notably Heetfeld and colleagues (2015), showed that these tumours, usually pancreatic and usually with a Ki-67 between 20 and 55 percent, responded poorly to platinum-etoposide but survived longer, and the NORDIC NEC series (2013) had already found that a Ki-67 below 55 percent predicted the same pattern. The WHO classified pancreatic NET G3 as a distinct entity in 2017 and extended it to the whole digestive system in 2019; molecularly these tumours carry the MEN1, DAXX and ATRX changes of neuroendocrine tumours and retain p53 and Rb, whereas carcinoma loses them, which is why p53 and Rb immunohistochemistry is now used when morphology is ambiguous.\n\nTreatment evidence is thin because the entity is new and small. Capecitabine with temozolomide is the most used chemotherapy, on the basis of pancreatic tumour data from E2211 and retrospective grade 3 series, and everolimus and sunitinib are used with less evidence. Somatostatin receptor PET is usually positive, often with FDG avidity as well, and this dual pattern makes radioligand therapy plausible: NETTER-2 (Lancet 2024) was designed to include grade 3 tumours with a Ki-67 up to 55 percent alongside higher grade 2 tumours, and first-line lutetium-177 dotatate lengthened progression-free survival from 8.5 to 22.8 months across the 226 patients, the first randomised evidence in this group. COMPOSE randomises well-differentiated aggressive grade 2 and grade 3 gastroenteropancreatic tumours between 177Lu-edotreotide and CAPTEM, everolimus or FOLFOX, and is due to report in 2027.\n\nThe practical decisions are about tempo and receptor status. Tumours near the upper end of Ki-67, growing fast or losing receptor expression on PET are treated more like carcinoma with platinum-etoposide, while receptor-positive tumours with slower tempo are treated like grade 2 tumours with radioligand therapy or CAPTEM. Surgery and liver-directed therapy are used as for other well-differentiated tumours when disease is limited. Whether grade 3 tumours should be graded further, and where the Ki-67 line between tumour and carcinoma really lies, remain open.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"NETTER-2 (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00701-3"},{"label":"Heetfeld et al. (Endocrine-Related Cancer 2015)","url":"https://doi.org/10.1530/ERC-15-0119"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":[],"cancers":[],"sections":[],"technologies":["sstr-pet","prrt","pet","radioligand-therapy"],"targets":["sstr2","tp53","menin"],"drugs":["lutathera","capecitabine-temozolomide","everolimus","sunitinib","platinum-etoposide","itm-11","octreotide-lanreotide"],"companies":[],"institutions":[],"pathways":[],"terms":["net-grade-ki67","tumour-differentiation","chromogranin-a","prrt-term"],"trials":["nct03972488","nct04919226","compete"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A small fraction of neuroendocrine neoplasms, most often pancreatic; recognised as a separate entity by the WHO in 2017 for the pancreas and 2019 for the whole digestive system after series showed it outlives neuroendocrine carcinoma and responds less to platinum.","subtypes":["Grade 3 well-differentiated pancreatic NET (the commonest site)","Grade 3 well-differentiated small intestinal and other gastroenteropancreatic NET","NET G3 with Ki-67 20 to 55 percent, somatostatin receptor-positive (radioligand candidates)","NET G3 with high FDG avidity or falling receptor expression (carcinoma-like behaviour)","Grade 2 to grade 3 progression within a known neuroendocrine tumour"],"biomarkers":["Ki-67 above 20 percent (usually 20 to 55 percent) with well-differentiated morphology","Retained p53 and Rb by immunohistochemistry (abnormal in carcinoma)","Somatostatin receptor PET, usually positive, with FDG PET for dual-tracer assessment","Chromogranin A (monitoring)","MEN1, DAXX and ATRX alterations (tumour lineage, research)","MGMT status (CAPTEM response, investigational)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Morphology, Ki-67 and p53 or Rb immunohistochemistry to separate grade 3 tumour from carcinoma; somatostatin receptor and FDG PET together.","refs":["net-grade-ki67","tumour-differentiation","sstr-pet","pet","tp53"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, somatostatin receptor-positive","approach":"Lutetium-177 dotatate first line for Ki-67 up to 55 percent (NETTER-2); somatostatin analogue alongside.","refs":["lutathera","nct03972488","prrt","octreotide-lanreotide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, shrinkage needed or receptor-negative","approach":"Capecitabine with temozolomide; everolimus or sunitinib for pancreatic tumours; platinum-etoposide for carcinoma-like tempo or Ki-67 near 55 percent.","refs":["capecitabine-temozolomide","everolimus","sunitinib","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Trials","approach":"COMPOSE: 177Lu-edotreotide against CAPTEM, everolimus or FOLFOX in aggressive grade 2 and grade 3 gastroenteropancreatic tumours.","refs":["nct04919226","itm-11"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Limited disease","approach":"Resection and liver-directed therapy as for other well-differentiated tumours.","refs":["hepatectomy","thermal-ablation","tace","liver-directed-therapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["The 2017 and 2019 WHO classifications turned a pathology observation into a treatable category and spared these patients platinum they did not benefit from.","NETTER-2 supplied the first randomised evidence in grade 3 tumours and put radioligand therapy first line.","p53 and Rb immunohistochemistry and dual-tracer PET give practical tools for the ambiguous case."],"history":[{"year":2013,"title":"NORDIC NEC: Ki-67 below 55 percent marks a less platinum-sensitive, longer-surviving group","refs":[]},{"year":2015,"title":"Heetfeld and colleagues characterise well-differentiated grade 3 tumours as distinct from carcinoma","refs":[]},{"year":2017,"title":"WHO classification of pancreatic tumours creates NET G3","refs":["net-grade-ki67"]},{"year":2019,"title":"WHO digestive system classification extends NET G3 to the whole gut","refs":["net-grade-ki67"]},{"year":2021,"title":"COMPOSE opens: 177Lu-edotreotide against chemotherapy or everolimus in aggressive grade 2 and grade 3 tumours","refs":["nct04919226","itm-11"]},{"year":2024,"title":"NETTER-2: first-line lutetium-177 dotatate in grade 2 to 3 tumours with Ki-67 up to 55 percent","refs":["nct03972488","lutathera"]}],"pipeline":["nct04919226","itm-11","lutathera","capecitabine-temozolomide","idea-net-dosimetry-prrt"],"openProblems":["The Ki-67 boundary between grade 3 tumour and carcinoma is not sharp, and some cases can only be settled by molecular testing.","No trial has been run in grade 3 tumours alone; NETTER-2 and COMPOSE mix them with grade 2.","Whether platinum-etoposide, CAPTEM or radioligand therapy should come first in the fastest grade 3 tumours is unknown."],"parent":"neuroendocrine"},"route":"/cancers/grade-3-net/","neighbours":{"technology":[{"id":"prrt","kind":"technology","name":"Peptide receptor radionuclide therapy (PRRT)","route":"/technologies/prrt/"},{"id":"pet","kind":"technology","name":"PET (positron emission tomography)","route":"/technologies/pet/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"},{"id":"thermal-ablation","kind":"technology","name":"Thermal ablation (RFA, microwave, cryo)","route":"/technologies/thermal-ablation/"},{"id":"tace","kind":"technology","name":"Transarterial chemoembolisation (TACE)","route":"/technologies/tace/"}],"target":[{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"sstr2","kind":"target","name":"Somatostatin receptor 2","route":"/targets/sstr2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"itm-11","kind":"drug","name":"177Lu-edotreotide","route":"/drugs/itm-11/"},{"id":"capecitabine-temozolomide","kind":"drug","name":"Capecitabine + temozolomide (CAPTEM)","route":"/drugs/capecitabine-temozolomide/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"lutathera","kind":"drug","name":"Lutetium-177 dotatate","route":"/drugs/lutathera/"},{"id":"platinum-etoposide","kind":"drug","name":"Platinum + etoposide (EP / CE)","route":"/drugs/platinum-etoposide/"},{"id":"octreotide-lanreotide","kind":"drug","name":"Somatostatin analogues (octreotide, lanreotide)","route":"/drugs/octreotide-lanreotide/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}],"term":[{"id":"chromogranin-a","kind":"term","name":"Chromogranin A","route":"/terms/chromogranin-a/"},{"id":"hepatectomy","kind":"term","name":"Hepatectomy (liver resection)","route":"/terms/hepatectomy/"},{"id":"liver-directed-therapy","kind":"term","name":"Liver-directed therapy (TACE, TARE, HAI, ablation)","route":"/terms/liver-directed-therapy/"},{"id":"net-grade-ki67","kind":"term","name":"Neuroendocrine tumour grade (Ki-67) and WHO classification","route":"/terms/net-grade-ki67/"},{"id":"prrt-term","kind":"term","name":"PRRT (peptide receptor radionuclide therapy)","route":"/terms/prrt-term/"},{"id":"tumour-differentiation","kind":"term","name":"Tumour differentiation (well / moderately / poorly differentiated)","route":"/terms/tumour-differentiation/"}],"trial":[{"id":"compete","kind":"trial","name":"COMPETE","route":"/trials/compete/"},{"id":"nct04919226","kind":"trial","name":"Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE","route":"/trials/nct04919226/"},{"id":"nct03972488","kind":"trial","name":"Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET","route":"/trials/nct03972488/"}],"idea":[{"id":"idea-net-dosimetry-prrt","kind":"idea","name":"Dosimetry-personalised PRRT instead of four fixed cycles","route":"/ideas/idea-net-dosimetry-prrt/"}],"cancer":[{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"}]}}